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Hormonal Contraception and Breast Cancer: Accounting for Age at Diagnosis
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GYNAECOLOGY
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HORMONAL CONTRACEPTION AND BREAST CANCER: ACCOUNTING FOR AGE AT DIAGNOSIS John A. Collins, Departments of Obstetrics and Gynaecology, Clinical Epidemiology and Biostatistics, McMaster University
ABSTRACT
Background: Breast cancer risk is altered by endogenous hormonal activity and there is evidence of a link with hormonal contraception. This paper evaluates existing evidence on the association between hormonal contraceptive use and the risk of breast cancer with respect to age at the time of diagnosis. Methods: A search was conducted for studies which provided estimates of the relative risk ( RR) of breast cancer among hormonal contraceptive users compared with non-users by age at the time of diagnosis. Ten studies reported on ural contraceptive use and three studies on depo-medroxy progesterone acetate (DMPA) use. The relationship between the RR of breast cancer in users and age at the time of diagnosis was estimated by means of weighted least squares regression and with the use of procedures to estimate typical odds ratios. Results: The RR and 95 percent confoience interval ( 95 %CI) of breast cancer among oral contraceptive users compared with non-users was 1.60 ( 1.35-1.90) (p <0.0001) in studies involving 1,680 cancer patients less than 35 years of age at the time of breast cancer diagnosis, and 0.89 (0.82-0.97) (p = 0.007) in studies involving 4,156 cancer patients aged 45 to 54 years. The RR (95%CI) of breast cancer among DMPA users compared with non-users was 1.91 (1.38-2.63) (p = 0.0001) in studies involving 257 cancer patients aged less than 35 years at the time of breast cancer diagnosis, and 0.94 (0.26-1.17) (p = 0.31) in studies involving 2,000 cancer patients aged 35 or more years. An association with longer duration of use was found in only three studies. Conclusions: Recent studies of hormonal contraception and breast cancer suggest that the increased risk of breast cancer among hormonal contraceptive users is confined to women who experience breast cancer at a young age. The risk of breast cancer among older women who have used hormonal contraceptives is either unchanged or slightly reduced. RESUME
Introduction: L' activit€ hormonale endogene influe sur le risque de cancer du sein et il semble que ce soit aussi le cas de Ia contraception hormonale. Cet article evalue les donnees actuelles sur le risque du cancer du sein associe al' utilisation contraceptive d' horrnrmes, en fonction de l' ilge au moment du diagnostic. Methodes: L' auteur a procede a une recherche documentaire des etudes foumissant une evaluation du risque relatif (RR) de cancer du sein chez les utilisatrices de contraceptifs horrnonaux par rapport aux non-utilisatrices, en function de l' ilge au moment du diagnostic. Dix etudes portaient sur l' utilisation des contraceptifs oraux et trois autres sur l' utilisation de l' acetate de medroxyprogesterone (DMPA) . La relation entre le RR de cancer du sein chez les utilisatrices et l' ilge au moment du diagnostic a ete evaluee au moyen de Ia regression ponderee (methode des moindres carres) et avec l' utilisation de diverses methodes pour evaluer les rapports de cotes types. Resultats: Le RR ( intervalle de confiance 95 %) de cancer du sein chez les utilisatrices de contraceptifs oraux par rapport aux non-utilisatrices etait de 1,60 (1 ,35-1 ,90) (p < 0,0001) dans les etudes menees aupres de 1 680 patientes cancereuses ayant mains de 35 ans au
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JANUARY 1995
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Highly reliable bladder control .•. Urispas is highly effective in the treatment of both urge and frequency incontinence and has been shown to significantly improve the clinical symptoms in women affected by the urge syndrome.1•3
...with virtually no "intolerable" side effects Arecent study has shown that the incidence and intensity of side effects is significantly greater with oxybutynin than with flavoxate. The most common side effects with oxybutynin vs flavoxate were dry mouth/dry eyes (87.8% vs 2.4%), stomach pain (41.5% vs 21.9%) and nausea/vomiting (21.9% vs 4.8%). 1
(Fiavoxate Hydrochloride)
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sc1ence Pharmascience Inc. Montreal, Que.
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' ' ' moment du diagnostic de cancer du sein et de 0,89 (0,82- 0,97) (p= 0,007) dans les etudes portant sur 4 156 patientes cancereuses agees de 45 a54 ans. Le RR (IC 95 %) de cancer du sein chez les utilisatrices de DMPA par rapport aux non-utilisatrices etait de 1,91 (1 ,38 -2,63) (p = 0,0001) dans les etudes menees aupres de 257 patientes cancereuses agees de mains de 35 ans au moment du diagnostic de cancer du sein et 0,94 (0,26- 1, 17) (p= 0,31) dans les etudes portant sur 2 000 patientes cancereuses agees de 35 ans ou plus. On a trouve un lien entre le cancer du sein et une utilisation prowngee dans seulement trois etudes. Conclusion: Les etudes recentes de Ia contraception hormonale et du cancer du sein suggerent que l' augmentation du risque de cancer du sein chez les utilisatrices de contraceptifs hormonaux se limite aux femmes atteintes d' un cancer du sein aun jeune age. Le risque de cancer du sein chez les femmes plus agees qui ont utilise des contraceptifs hormonaux est soit inchange, soit legerement reduit.
J SOGC 1995;17:33-42 KEY WORDS Oral contraception, depo-medroxy progesterone acetate, breast cancer, meta-analyses.
INTRODUCTION
METHODS
Several breast cancer risk factors are associated with ovarian hormone activity, and, therefore, an association with hormonal contraception would be credible. Studies have failed to establish a consensus, however, although there is evidence accumulating of a link between the use of oral contraceptives (OCs) and increased breast cancer risk in women less than 45 years of age. 1•2 Depo-medroxy progesterone acetate (DMPA) use also has been associated with increased breast cancer risk in young women, but for both types of hormonal contraception, there is no apparent effect on the risk for older women. 1·4 A link between OCs and breast cancer is plausible because oral contraceptives stimulate proliferation in breast epithelial tissue, and this may represent a step in carcinogenesis.' Studies have not evaluated the effect of DMPA in normal breast tissue, but a similar response would be consistent with the pharmacology of this preparation. The reported effects vary substantially, howe··er, from 40 percent risk reduction to a 300 percent increase in the risk for a diagnosis of breast cancer before 35 years of age. 6•7 Although breast cancer incidence is very low in young women, if the true effect were as great as 300 percent, it would have a bearing on contraceptive decisions. Because of this uncertainty, it is timely to consider OC and DMPA use in relation to the incidence of breast cancer in young women. This paper evaluates existing evidence on the association between hormonal contraceptive use and the risk of breast cancer in young women.
Studies addressing the association between hormonal contraception and breast cancer were identified by means ofMedline searches to July 1994. Additional studies were found in major reviews and in the references of the retrieved reports. Studies were eligible if the data included relative risks (RR) and 95 percent confidence intervals (95% CI) within specific age groups, or if the data defined the number of cases and controls who were exposed and unexposed within specific age groups. Studies based on women who were more than 35 years of age in 1965 were not used because the data included too few hormonal contraceptive users. For studies which gave rise to several publications, only the most recent, eligible report was used. Eligible reports of hormonal contraception included ten studies of OC use and three studies of DMPA use. Four reports provided data on oral contraceptives containing only progesterone derivatives but none of these included age-specific information on the relative risk. The published reports evaluated the effect of age at diagnosis, making use of the following major age groupings: less than 3 5 years, 3 5 to 44 years, 4 5 to 54 years; or less than 40 years, 40 to 49 years, and 50 to 59 years. Although some studies included women as young as 21 years, in practice, very few cases or controls were less than 25 years of age and the lowest age for the categories less than 35 years, and less than 40 years was considered to be 25 years. For the regression analyses described below, a single age point was chosen within each reported age interval. In order to approximate the median incidence point within each age group, and recognizing that
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JANUARY 1995
' ' ' breast cancer incidence rises dramatically within the specified ages, the chosen age point was set at the 67th percentile of each age interval. Also, in these regression analyses, year one was set at 25 years of age, rather than at thelarche, because average age at thelarche was not routinely reported and because measurable breast cancer risks begin at age 25. Separate meta-analyses were conducted for OC use and DMPA use. Each meta-analysis consisted of two procedures. Initially, the effect of age at diagnosis was estimated by weighted least squares regression: the naturallog of the reported relative risk against the median age at diagnosis.' This analysis made use of the adjusted relative risk estimate as reported with its 95 percent confidence interval. Supplemental analyses were conducted to fit the most appropriate equation. For these analyses, each relative risk was weighted by the inverse of its variance. In this way, more precise RR estimates were given greater weight in the regression analysis. The second procedure combined the two-by-two tables within each age group. This was also repeated for each type of exposure (OC or DMPA). For each type of exposure, the log risk was obtained as a weighted combination of the logarithms of the reported risks within specified age groups. These estimates with their standard errors were converted to relative risks and 95 percent confidence intervals. The significance of the estimates was based on Mantel-Haenszel statistics.9 Also, for each estimate, a Breslow-Day test of homogeneity was calculated. 10
FIGURE 1
35
30
40
45
50
55
60
Age at Diagnosis (Years)
Relative risk of breast cancer among oral contraceptive users by age at diagnosis: adjusted relative risks (95% Cl) as reported, 0; weighted linear regression,----
age 25. The estimated RR based on this equation was 1.25 at 35 years of age and 0.99 at 50 years of age. Eight studies involving 11,085 women with breast cancer included two-by-two tables which could be combined to obtain risk estimates within specified age groups. 1•6 ·1 · 11 ' 11 · 15 ·' 6 Of these breast cancer cases, 5,3 7 4 (48.5%) had used oral contraceptives, compared with 9,751 (42.6%) of the 22,874 controls. The typical relative risks are plotted in Figure 2. For women less than 35 years of age, the typical RR (95%CI) based on this analysis was 1.60 ( 1.35-1.90) (p < 0.0001) in studies involving 1,580 cancer patients. For women aged 45 to 54 years, the typical RR was 0.89 (0.82-0.97) (p = 0.007) in studies involving 4,156 cancer patients.
RESULTS
FIGURE 2
ORAL CONTRACEPTIVE EXPOSURE.
Ten studies involving 12,898 women with breast cancer were included in the regression analysis of the adjusted relative risks of breast cancer among oral contraceptive users and age at diagnosis.'A· 6· 7· 11 ' 16 In seven of the ten studies, there was no significant increase in the relative risk in relation to duration of OC use. The studies yielded 2 7 individual relative risk estimates which are plotted in Figure 1. There was a significant downward trend in log relative risk with age (r = -.71, p < 0.001), and age at diagnosis accounted for 51 percent of the variability in log relative risk. The weighted least squares estimate of the risk in relation to age at diagnosis was expressed by the following equation: ln(RR) = 0.38-0.015 x (years) where year one is at
JOURNAL SOGC
2.0
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25
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35
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-- - - - - - - - - - - - · - - - _______________ ..!
40
45
50
55
60
Age at Diagnosis (years) Typical risk of breast cancer among oral contraceptive users within reported groups by age at diagnosis: typical odds ratio and 95% Cl.
36
JANUARY 1995
0.
' ' ' estimates were computed for women less than 35 years of age, and for those aged 35 or more years. One study made use of age groups 25 to 3 9 ( 41 cases) and 40 or more years (107 cases). 6 The data for women 25 to 39 years of age were considered with the 25 to 35 year age group, and the data for women aged 40 or more years were considered with the 35 or greater age group. The typical RR (95%CI) based on this analysis was 1.91 ( 1.38-2.63) (p = 0.0001) in studies involving 257 cancer patients less than 35 years of age, and 0.93 (0.79-1.08) (p = 0.31) in studies involving 2,000 cancer patients aged 35 years or more. These estimates are shown in Table 1 together with estimates of OC risks based on a similar re-grouping of the age at diagnosis.
TABLE 1 TYPICAL RISK ESTIMATES FOR BREAST CANCER AMONG OC AND DMPA USERS EXPOSURE
AGE GROUP
RR (95% Cl)
P VALUE
oc oc
<35 years
1.54 (1.34-1.76)
<0.0001
:>34years
0.95 (0. 90-1.01)
0.12
DMPA
<35 years
1.91 (1.38-2.63)
0.0001
DMPA
>34 years
0.93 (0.79-1.08)
0.31
DEPO-MEDROXY PROGESTERONE ACETATE EXPOSURE
Three studies involving 2,257 patients with breast cancer were identified for this meta-analysis. 6·1718 Only 299 (13.2%) of these cancer cases and 1,935 (12.4%) of the 15,62 7 controls had used DMPA. None of these studies found a significant increase in risk in relation to duration of DMPA use. The downward trend in log relative risk with age at diagnosis is not significant (r = -.20, p = 0.43 ), and age at diagnosis accounts for only four percent of the variance in log RR (Figure 3). The risk estimate equation for DMPA was ln(RR) = 0.35-0.009 x (years) where year one is at age 25. The estimated RR based on this equation was 1.30 at 35 years of age and 1.14 at 50 years of age. Each of these studies included two-by-two tables for the computation of typical risk estimates. Because there were fewer studies available and a relatively small number of DMPA-exposed breast cancer cases, typical risk
ATTRIBUTABLE RISK
The results of the OC meta-analyses were then applied to estimate the risk of breast cancer that is attributable to OC use. Recently reported annual incidence rates by five year age groups from Alberta provide data to approximate the cumulative breast cancer incidence to age 35 (17 cases per 10,000 women). 19 From 35 to 54 years (the age of the oldest women included in most of the hormonal contraceptive studies), the cumulative incidence is 244 cases per 10,000 women. Although OC use may be a factor in recent breast cancer incidence, there has been little change over the years in reported age-incidence patterns. Therefore, for the present purpose the observed age-incidence data will be assumed to apply in a theoretical population of 10,000 women who are not OC users. The effect of OC use can then be computed for a theoretical population of 10,000 OC users. Thus, among 10,000 non-users, 17 women will have a diagnosis of breast cancer before they reach 35 years of age; among 10,000 oral contraceptive users a total of 26 women will have such a diagnosis, or nine additional women with breast cancer (Table 2). This reflects the baseline rate multiplied by the odds ratio (17 times 1.54 ); the confidence interval indicates that the excess of cases among users is extremely unlikely to be more than 13 women. During the next twenty years, the expected number of breast cancer cases among the 10,000 nonusers will be 244, compared with 232 cases among oral contraceptive users (the expected 244 cases times 0.95 = 232). Among the 10,000 OC users, the computed net reduction would be three breast cancer cases before 55 years of age.
FIGURE3
0.1----~
25
30
35
40
45
50
55
60
Age at Diagnosis (years) Relative risk of breast cancer among DMPA users by age at diagnosis: adjusted relative risks (95% Cl) as reported, 0; weighted linear regression,----
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JANUARY 1995
MEETING THE CHALLENGE OF THE NEWCOMERS
NORGESTREL GROUP ORAL CONTRACEPTIVES THE MARKET LEADER
2
vs
THE NEWCOMERS
MARVELON" ORTHO-CEPP CYCLENl TRI-CYCLENl TRIPHASIL PROVIDES EXCELLENT CYCLE CONTROL WITH LOWER INCIDENCE OF BTB AND SPOTTING 3•4•5 12%
PERCENTAGE OF BREAKTHROUGH BLEEDING EPISODES3•4•5 mMarvelon'/ mOrtho-Cept t wcyclen t
• mTriphasil
10
CYCLES
• mTri-Cyclen t ...........................................................................................................
12%
............................................................................................................ 10
4
3
2
5
Adapted from Lachnit-Fixson et al.' n = 555 women 3,060 cycles p<0.001 for all cycles
6
2
3
4
Adapted from Kafrissen' Cycles 5 and 6 n/a n = 1,473 women 19,078 cycles
2
3
4
5
6
Adapted from Gauthier et al.' n = 661 women 6,511 cycles
• Marvelon (desogestrellethinyl estradiol) is a registered trademark of Organon Canada Ltd. t Ortho-Cept (desogestrel/ethinyl estradiol), Cyclen and Tri-Cyclen (norgestimate/ethinyl estradiol) are registered trademarks of Ortho-McNeillnc.
TRIPHASIL IS A FORMULATION WITH ANTIANDROGENIC EFFECTS, INCREASING SHBG LEVELS, REDUCING PLASMA ANDROGEN LEVELS AND THUS IMPROVING ACNE 6,7 ".. .this product [Triphasi/] is recommended in women requiring contraception who also have idiopathic acne. "7 PERCENTAGE INCIDENCE OF ACNE'
"The decrease in ovarian/adrenal androgen levels and the increase in SHBG levels, which are distinctly an estrogenic response, indicate that this triphasic formulation has no androgenic properties, but, rather, estrogenic and antiandrogenic effects. "7 n = 491 women
n = 486 women
3,678 cycles
Adapted from Allen et al.
TRIPHASIL HAD A LOWER INCIDENCE OF NUISANCE SIDE EFFECTS 3 TRIPHASIL Amenorrhea Weight gain (more than 2kg) Breast tenderness Discontinuation
0.2% 5.2% 2.2% 6.1%
MARVELON/ ORTHO-CEPT
An unexcelled clinical record
0.9% 16.7% 5.4% 11.9%
"An optimal oestrogen-progestogen ratio... may be more important for the overall effect of the preparation than partial qualities of the hormonal components. "3
' ' ' appear to relate to one of two mechanisms: variability in the number of potential cancer cells seems CASES OF BREAST CANCER THAT MAY BE to explain some risks, such as the international ATTRIBUTABlE TO OC USE differences in incidence; variability in the susceptiBreast cancer Attributable OC Breast cancer bility of those cells may explain hormonally assocases/10,000 cases/1 0,000 RRwith OC cases/10,000 Age at ciated differences, such as the increased risk with users non-users OC users diagnosis use greater age at first birth. 21 There is a short term 1.54 +9 17 <35 years 26 increase in breast cancer risk after a first birth that 244 232 0.95 ·12 35-54yrs be the effect of high hormone levels during may 261 258 All <54yrs ·3 pregnancy. 24 The endogenous hormones appear to induce further growth in breast cells that have already The data on DMPA are based on fewer studies and undergone malignant transformation. Pregnancy also smaller numbers of exposed cases and controls and, confers long-term protection which appears to reflect therefore, the DMPA evidence is less secure than the advanced maturing and terminal differentiation of breast OC effect. The computed attributable risk consists of an tissue with the consequent reduction in malignant excess of 15 cases before age 35 among 10,000 DMPA potential. 24 ' 25 users (1.91 times the expected 17/10,000), and a reduction These endogenous hormonal actions seem to result of 17 cases from age 35 to 54 (0.93 times the expected from both estrogen and progesterone exposure. Studies 244/10,000). Among the 10,000 DMPA users, the comof normal breast tissue have indicated that epithelial proputed net reduction would be two breast cancer cases liferation is maximal in the luteal phase under the influbefore 55 years of age. ence of progesterone. 5•26 Maximal breast tissue growth DISCUSSION also was observed in the last half of hormonal contraception cycles, and these responses to endogenous and In this analysis of the existing literature on the breast exogenous hormones decrease with age, notably during cancer risk attributable to hormonal contraceptives, the the first ten years after thelarche. 5 This change in breast typical risk for OC use was increased for women less than tissue responses is consistent with a shift in the suscep35 years of age, there was a significant downward trend tibility of breast cells to malignant alteration, and given in the OC-associated risk after 35 years of age, and a the long latency period for breast cancer, could underly small net reduction in the computed cumulative breast the cross-over in exogenous hormone risks that was seen cancer risk for OC users compared with non-users. If the after 35 years of age. protection associated with hormone use continues If the influence of endogenous hormones is similar, beyond the age of 54 years, then the overall protective then pregnancy should have an analagous effect. Two effect of hormonal contraception would be much greater. recent large studies 24 ' 25 confirm the indication from earThe oral contraceptives considered in the analysis were lier studies that pregnancy increases the short term risk combinations of estrogenic and progestogenic comof breast cancer in young women, 27 ·'~ Among 91,523 U.S. pounds. Although DMPA has only progestogenic nurses, the increase in breast cancer incidence for parous activity, the observations among DMPA users mirrored women remained elevated for 20 to 30 years after the those among OC users. The analysis confirms the most first birth, compared with nulliparous women, but the likely assumptions about breast cancer risk among oral cumulative incidence to age 70 was lower for the parous contraceptive users, '· 20 ' 22 and it provides precise estiwomen." In a case-control study linking 12,666 breast mates of the downward trend in the OC effect on breast cancer patients and 62,121 age-matched controls from cancer incidence. the Swedish Fertility Registry, pregnancy had a similar The presence of a cross-over from increased risk to dual effect on cancer risk, which was increased trandecreased risk explains in part the conflicting findings of siently after childbirth and decreased in later years. 24 The earlier studiesY This alteration in the effect of exogeSwedish data for uniparous women are shown in Figure nous hormones over time is perplexing, but some recent 4 together with estimates from the present meta-analysis. publications discuss proposed mechanisms that seem bioThus, the existing evidence suggests that endogenous logically and epidemiologically sound. Breast cancer risks
TABLE2
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40
JANUARY 1995
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+-----+.
and exogenous hormones have comparable effects on breast cancer risk: an increased risk in young women which declines gradually. One explanation for the association between hormonal contraception and breast cancer at a young age is that contraceptive use may delay the first birth. In studies that do not adjust for age at first birth, contraceptive use might express the increased risk that is associated with delayed first birth. This interpretation is unsatisfactory, however, because the association between hormonal contraception and breast cancer was present, although reduced in magnitude, even in studies that adjusted for age at first birth. 11 ·15 ·" A second explanation might be that estrogenic and progestogenic hormones aetas promoters of breast epithelial growth, an action that generally depends on prolonged exposure. A promoter mechanism would be associated with a greater risk after longer duration of exposure, but such an effect was present in only three of the OC studies.w·15 Moreover, in one OC study and one DMPA study, shorter duration of use was associated with increased risk. 7·w A more likely explanation is that pregnancy and hormonal contraception decrease the length of the pre-clinical latent stage in cancers which have already developed, thus causing them to be recognized sooner. Therefore, it seems reasonable to hypothesize that hormonal contraception for the majority of women
JOURNAL SOGC
is harmless or beneficial with respect to breast cancer, although in a small sub-set of women who are as yet unidentifiable, breast cancer is more likely to be diagnosed soon after exposure to these hormones. The existing data do not separate satisfactorily the effect of late first birth from the effect of using oral contraception which is the most common means of delaying conception. Oral contraceptive pills are used by the majority of young women in Western countries. In the UK National Case Control Study, 91 percent of cases and 89 percent of controls had used oral contraceptives for an average total duration of 5.6 years." Because OC use is so prevalent, the attributable risks in Table 2 approximate the population effect, and imply that breast cancer risk should not be a crucial factor in contraceptive decisions for the typical patient. Depo-medroxy progesterone acetate use is much less prevalent ( 12% of the 11,890 controls in the WHO study), and the associated menstrual changes are more problematic, but it provides effective contraception. 1'· 29 On the best available evidence, the DMPA-associated breast cancer risk mirrors that of oral contraception and should not govern clinical or regulatory policy decisions. REFERENCES 1.
Romieu I, Berlin JA. Colditz GA. Oral contraceptives and breast cancer. Review and meta-analysis. Cancer 1990; 66:2253-63.
2.
Rushton L, Jones DR. Oral contraceptive use and breast cancer risk: a meta-analysis of variations with age at diagnosis, parity and total duration of oral contraceptive use.
3. 4.
5.
6.
Br J Obstet Gynaecol 1992;99:239-46. Ewertz M. Oral contraceptives and breast cancer risk in Denmark. EurJ Cancer 1992;28A:1176-81. White E, Malone KE, Weiss NS, Daling JR. Breast cancer among young U.S. women in relation to oral contraceptive use. J Natl Cancer lnst 1994;86:7:505-14. Anderson TJ, Battersby S, King RJB, McPherson K, Going JJ. Oral contraceptive use influences resting breast proliferation. Hum Pathol1989;20:1139-44. Lee NC, Rosero-Bixby L, Oberle MW, Grimaldo C, Whatley AS, Rovira EZ. A case-control study of breast cancer and hormonal contraception in Costa Rica. J Natl Cancer lnst 1987;79:6:1247-54.
41
7.
Miller DR, Rosenberg L, Kaufman OW, Stolley P, Warshauer ME, Shapiro S. Breast cancer before age 45 and oral contraceptive use: new findings. Br J Obstet Gynaecol 1981 ;88:1016-20.
8.
Kleinbaum DG, Kupper LL, Muller KE. Applied regression analysis and other multivariate methods. 2nd ed. Boston: PWS-Kent Publishing Company, 1988:41-79.
JANUARY 1995
' ' ' 9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23. 24.
25. Rosner B, Colditz GA, Willett WC. Reproductive risk factors in a prospective study of breast cancer. Am J Epidemiol 1994; 139:819-35. 26. Meyer JS. Cell proliferation in normal human breast ducts, fibroadenomas, and other ductal hyperplasias measured by nuclear labeling with tritiated thymidine. Hum Pathol1977;8:1:67-81. 27. Bruzzi P, Negri E, LaVecchia C, et al. Short term increase in risk of breast cancer after term pregnancy. Br Med J 1988;297: 1096-8. 28. Williams EM I, Jones L, Vessey MP, McPherson K. Short term increase in risk of breast cancer associated with full term pregnancy. Br Med J 1990;300:578-9. 29. Klitsch M. Injectable hormones and regulatory controversy: an end to the long-running story? Fam Plann Perspect 1993;25:1 :37-40.
Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer lnst 1959;22:719-48. Breslow NE, Day NE. Volume 1: The analysis of casecontrol studies. In Davis W, ed. Statistical Methods in Cancer Research. Lyon: International Agency for Research on Cancer, 1980:136-57. UK National Case-Control Study Group, Chilvers C, McPherson K, Peto J, Pike MC. Oral contraceptive use and breast cancer risk in young women. Lancet 1989;i:973-82. Rosenberg L, Palmer JR, Clarke EA, Shapiro S. A casecontrol study of the risk of breast cancer in relation to oral contraceptive use. Am J Epidemiol 1992; 136:12:1437-44. Stanford JL, Brinton LA, Hoover RN. Oral contraceptives and breast cancer: results from an expanded case-control study. Br J Cancer 1989;60:375-81. Weinstein AL, Mahoney MC, Nasca PC, Leske MC, Varma AO. Breast cancer risk and oral contraceptive use: results from a large case-control study. Epidemiology 1991; 24:353-8. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Breast cancer and combined oral contraceptives: results from a mutinational study. Br J Cancer 1990;61 :110-19. Wingo PA, Lee NC, Ory HW, Beral V, Peterson HB, Rhodes P. Age-specific differences in the relationship between oral contraceptive use and breast cancer. Cancer 1993;71 :1506-17. Paul C, Skegg DCG, Spears GFS. Depot medroxyprogesterone (Depo-Provera) and risk of breast cancer. Br Med J 1989;299:759-62. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Breast cancer and depotmedroxyprogesterone acetate: a multinational study. Lancet 1991 ;338:833-8. Bryant HE, Brasher PMA. Risks and probabilities of breast cancer: short-term versus lifetime probabilities. CMAJ 1994;150:2:211-16. Petitti DB, Porterfield D. Worldwide variations in the lifetime probability of reproductive cancer in women: implications of best-case, worst-case, and likely-case assumptions about the effect of oral contraceptive use. Contraception 1992;45:2:93-1 04. Prentice RL, Thomas DB. On the epidemiology of oral contraceptives and disease. Adv Cancer Res 1987; 49:285-401. Thomas DB. Oral contraceptives and breast cancer: review of the epidemiologic literature. Contraception 1991 ;43:6:597 -642. MacMahon B. Reproduction and cancer of the breast. Cancer 1993;71:3185-8. Lambe M, Hsieh C-C, Trichopoulos D, Ekbom A, Pavia M, Adami H-0. Transient increase in the risk of breast cancer after giving birth. N Engl J Med 1994;331 :5-9.
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GYNAECOLOGY
' ' ' ' ' '
HORMONAL CONTRACEPTION AND BREAST CANCER: ACCOUNTING FOR AGE AT DIAGNOSIS John A. Collins, Departments of Obstetrics and Gynaecology, Clinical Epidemiology and Biostatistics, McMaster University
ABSTRACT
Background: Breast cancer risk is altered by endogenous hormonal activity and there is evidence of a link with hormonal contraception. This paper evaluates existing evidence on the association between hormonal contraceptive use and the risk of breast cancer with respect to age at the time of diagnosis. Methods: A search was conducted for studies which provided estimates of the relative risk ( RR) of breast cancer among hormonal contraceptive users compared with non-users by age at the time of diagnosis. Ten studies reported on ural contraceptive use and three studies on depo-medroxy progesterone acetate (DMPA) use. The relationship between the RR of breast cancer in users and age at the time of diagnosis was estimated by means of weighted least squares regression and with the use of procedures to estimate typical odds ratios. Results: The RR and 95 percent confoience interval ( 95 %CI) of breast cancer among oral contraceptive users compared with non-users was 1.60 ( 1.35-1.90) (p <0.0001) in studies involving 1,680 cancer patients less than 35 years of age at the time of breast cancer diagnosis, and 0.89 (0.82-0.97) (p = 0.007) in studies involving 4,156 cancer patients aged 45 to 54 years. The RR (95%CI) of breast cancer among DMPA users compared with non-users was 1.91 (1.38-2.63) (p = 0.0001) in studies involving 257 cancer patients aged less than 35 years at the time of breast cancer diagnosis, and 0.94 (0.26-1.17) (p = 0.31) in studies involving 2,000 cancer patients aged 35 or more years. An association with longer duration of use was found in only three studies. Conclusions: Recent studies of hormonal contraception and breast cancer suggest that the increased risk of breast cancer among hormonal contraceptive users is confined to women who experience breast cancer at a young age. The risk of breast cancer among older women who have used hormonal contraceptives is either unchanged or slightly reduced. RESUME
Introduction: L' activit€ hormonale endogene influe sur le risque de cancer du sein et il semble que ce soit aussi le cas de Ia contraception hormonale. Cet article evalue les donnees actuelles sur le risque du cancer du sein associe al' utilisation contraceptive d' horrnrmes, en fonction de l' ilge au moment du diagnostic. Methodes: L' auteur a procede a une recherche documentaire des etudes foumissant une evaluation du risque relatif (RR) de cancer du sein chez les utilisatrices de contraceptifs horrnonaux par rapport aux non-utilisatrices, en function de l' ilge au moment du diagnostic. Dix etudes portaient sur l' utilisation des contraceptifs oraux et trois autres sur l' utilisation de l' acetate de medroxyprogesterone (DMPA) . La relation entre le RR de cancer du sein chez les utilisatrices et l' ilge au moment du diagnostic a ete evaluee au moyen de Ia regression ponderee (methode des moindres carres) et avec l' utilisation de diverses methodes pour evaluer les rapports de cotes types. Resultats: Le RR ( intervalle de confiance 95 %) de cancer du sein chez les utilisatrices de contraceptifs oraux par rapport aux non-utilisatrices etait de 1,60 (1 ,35-1 ,90) (p < 0,0001) dans les etudes menees aupres de 1 680 patientes cancereuses ayant mains de 35 ans au
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JANUARY 1995
the only solution to poorly tolerated incontinence medication! Frequency and intensity of side effects can force up to 30% of incontinent patients to abandon their prescribed medication 1
Highly reliable bladder control .•. Urispas is highly effective in the treatment of both urge and frequency incontinence and has been shown to significantly improve the clinical symptoms in women affected by the urge syndrome.1•3
...with virtually no "intolerable" side effects Arecent study has shown that the incidence and intensity of side effects is significantly greater with oxybutynin than with flavoxate. The most common side effects with oxybutynin vs flavoxate were dry mouth/dry eyes (87.8% vs 2.4%), stomach pain (41.5% vs 21.9%) and nausea/vomiting (21.9% vs 4.8%). 1
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' ' ' moment du diagnostic de cancer du sein et de 0,89 (0,82- 0,97) (p= 0,007) dans les etudes portant sur 4 156 patientes cancereuses agees de 45 a54 ans. Le RR (IC 95 %) de cancer du sein chez les utilisatrices de DMPA par rapport aux non-utilisatrices etait de 1,91 (1 ,38 -2,63) (p = 0,0001) dans les etudes menees aupres de 257 patientes cancereuses agees de mains de 35 ans au moment du diagnostic de cancer du sein et 0,94 (0,26- 1, 17) (p= 0,31) dans les etudes portant sur 2 000 patientes cancereuses agees de 35 ans ou plus. On a trouve un lien entre le cancer du sein et une utilisation prowngee dans seulement trois etudes. Conclusion: Les etudes recentes de Ia contraception hormonale et du cancer du sein suggerent que l' augmentation du risque de cancer du sein chez les utilisatrices de contraceptifs hormonaux se limite aux femmes atteintes d' un cancer du sein aun jeune age. Le risque de cancer du sein chez les femmes plus agees qui ont utilise des contraceptifs hormonaux est soit inchange, soit legerement reduit.
J SOGC 1995;17:33-42 KEY WORDS Oral contraception, depo-medroxy progesterone acetate, breast cancer, meta-analyses.
INTRODUCTION
METHODS
Several breast cancer risk factors are associated with ovarian hormone activity, and, therefore, an association with hormonal contraception would be credible. Studies have failed to establish a consensus, however, although there is evidence accumulating of a link between the use of oral contraceptives (OCs) and increased breast cancer risk in women less than 45 years of age. 1•2 Depo-medroxy progesterone acetate (DMPA) use also has been associated with increased breast cancer risk in young women, but for both types of hormonal contraception, there is no apparent effect on the risk for older women. 1·4 A link between OCs and breast cancer is plausible because oral contraceptives stimulate proliferation in breast epithelial tissue, and this may represent a step in carcinogenesis.' Studies have not evaluated the effect of DMPA in normal breast tissue, but a similar response would be consistent with the pharmacology of this preparation. The reported effects vary substantially, howe··er, from 40 percent risk reduction to a 300 percent increase in the risk for a diagnosis of breast cancer before 35 years of age. 6•7 Although breast cancer incidence is very low in young women, if the true effect were as great as 300 percent, it would have a bearing on contraceptive decisions. Because of this uncertainty, it is timely to consider OC and DMPA use in relation to the incidence of breast cancer in young women. This paper evaluates existing evidence on the association between hormonal contraceptive use and the risk of breast cancer in young women.
Studies addressing the association between hormonal contraception and breast cancer were identified by means ofMedline searches to July 1994. Additional studies were found in major reviews and in the references of the retrieved reports. Studies were eligible if the data included relative risks (RR) and 95 percent confidence intervals (95% CI) within specific age groups, or if the data defined the number of cases and controls who were exposed and unexposed within specific age groups. Studies based on women who were more than 35 years of age in 1965 were not used because the data included too few hormonal contraceptive users. For studies which gave rise to several publications, only the most recent, eligible report was used. Eligible reports of hormonal contraception included ten studies of OC use and three studies of DMPA use. Four reports provided data on oral contraceptives containing only progesterone derivatives but none of these included age-specific information on the relative risk. The published reports evaluated the effect of age at diagnosis, making use of the following major age groupings: less than 3 5 years, 3 5 to 44 years, 4 5 to 54 years; or less than 40 years, 40 to 49 years, and 50 to 59 years. Although some studies included women as young as 21 years, in practice, very few cases or controls were less than 25 years of age and the lowest age for the categories less than 35 years, and less than 40 years was considered to be 25 years. For the regression analyses described below, a single age point was chosen within each reported age interval. In order to approximate the median incidence point within each age group, and recognizing that
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' ' ' breast cancer incidence rises dramatically within the specified ages, the chosen age point was set at the 67th percentile of each age interval. Also, in these regression analyses, year one was set at 25 years of age, rather than at thelarche, because average age at thelarche was not routinely reported and because measurable breast cancer risks begin at age 25. Separate meta-analyses were conducted for OC use and DMPA use. Each meta-analysis consisted of two procedures. Initially, the effect of age at diagnosis was estimated by weighted least squares regression: the naturallog of the reported relative risk against the median age at diagnosis.' This analysis made use of the adjusted relative risk estimate as reported with its 95 percent confidence interval. Supplemental analyses were conducted to fit the most appropriate equation. For these analyses, each relative risk was weighted by the inverse of its variance. In this way, more precise RR estimates were given greater weight in the regression analysis. The second procedure combined the two-by-two tables within each age group. This was also repeated for each type of exposure (OC or DMPA). For each type of exposure, the log risk was obtained as a weighted combination of the logarithms of the reported risks within specified age groups. These estimates with their standard errors were converted to relative risks and 95 percent confidence intervals. The significance of the estimates was based on Mantel-Haenszel statistics.9 Also, for each estimate, a Breslow-Day test of homogeneity was calculated. 10
FIGURE 1
35
30
40
45
50
55
60
Age at Diagnosis (Years)
Relative risk of breast cancer among oral contraceptive users by age at diagnosis: adjusted relative risks (95% Cl) as reported, 0; weighted linear regression,----
age 25. The estimated RR based on this equation was 1.25 at 35 years of age and 0.99 at 50 years of age. Eight studies involving 11,085 women with breast cancer included two-by-two tables which could be combined to obtain risk estimates within specified age groups. 1•6 ·1 · 11 ' 11 · 15 ·' 6 Of these breast cancer cases, 5,3 7 4 (48.5%) had used oral contraceptives, compared with 9,751 (42.6%) of the 22,874 controls. The typical relative risks are plotted in Figure 2. For women less than 35 years of age, the typical RR (95%CI) based on this analysis was 1.60 ( 1.35-1.90) (p < 0.0001) in studies involving 1,580 cancer patients. For women aged 45 to 54 years, the typical RR was 0.89 (0.82-0.97) (p = 0.007) in studies involving 4,156 cancer patients.
RESULTS
FIGURE 2
ORAL CONTRACEPTIVE EXPOSURE.
Ten studies involving 12,898 women with breast cancer were included in the regression analysis of the adjusted relative risks of breast cancer among oral contraceptive users and age at diagnosis.'A· 6· 7· 11 ' 16 In seven of the ten studies, there was no significant increase in the relative risk in relation to duration of OC use. The studies yielded 2 7 individual relative risk estimates which are plotted in Figure 1. There was a significant downward trend in log relative risk with age (r = -.71, p < 0.001), and age at diagnosis accounted for 51 percent of the variability in log relative risk. The weighted least squares estimate of the risk in relation to age at diagnosis was expressed by the following equation: ln(RR) = 0.38-0.015 x (years) where year one is at
JOURNAL SOGC
2.0
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40
45
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60
Age at Diagnosis (years) Typical risk of breast cancer among oral contraceptive users within reported groups by age at diagnosis: typical odds ratio and 95% Cl.
36
JANUARY 1995
0.
' ' ' estimates were computed for women less than 35 years of age, and for those aged 35 or more years. One study made use of age groups 25 to 3 9 ( 41 cases) and 40 or more years (107 cases). 6 The data for women 25 to 39 years of age were considered with the 25 to 35 year age group, and the data for women aged 40 or more years were considered with the 35 or greater age group. The typical RR (95%CI) based on this analysis was 1.91 ( 1.38-2.63) (p = 0.0001) in studies involving 257 cancer patients less than 35 years of age, and 0.93 (0.79-1.08) (p = 0.31) in studies involving 2,000 cancer patients aged 35 years or more. These estimates are shown in Table 1 together with estimates of OC risks based on a similar re-grouping of the age at diagnosis.
TABLE 1 TYPICAL RISK ESTIMATES FOR BREAST CANCER AMONG OC AND DMPA USERS EXPOSURE
AGE GROUP
RR (95% Cl)
P VALUE
oc oc
<35 years
1.54 (1.34-1.76)
<0.0001
:>34years
0.95 (0. 90-1.01)
0.12
DMPA
<35 years
1.91 (1.38-2.63)
0.0001
DMPA
>34 years
0.93 (0.79-1.08)
0.31
DEPO-MEDROXY PROGESTERONE ACETATE EXPOSURE
Three studies involving 2,257 patients with breast cancer were identified for this meta-analysis. 6·1718 Only 299 (13.2%) of these cancer cases and 1,935 (12.4%) of the 15,62 7 controls had used DMPA. None of these studies found a significant increase in risk in relation to duration of DMPA use. The downward trend in log relative risk with age at diagnosis is not significant (r = -.20, p = 0.43 ), and age at diagnosis accounts for only four percent of the variance in log RR (Figure 3). The risk estimate equation for DMPA was ln(RR) = 0.35-0.009 x (years) where year one is at age 25. The estimated RR based on this equation was 1.30 at 35 years of age and 1.14 at 50 years of age. Each of these studies included two-by-two tables for the computation of typical risk estimates. Because there were fewer studies available and a relatively small number of DMPA-exposed breast cancer cases, typical risk
ATTRIBUTABLE RISK
The results of the OC meta-analyses were then applied to estimate the risk of breast cancer that is attributable to OC use. Recently reported annual incidence rates by five year age groups from Alberta provide data to approximate the cumulative breast cancer incidence to age 35 (17 cases per 10,000 women). 19 From 35 to 54 years (the age of the oldest women included in most of the hormonal contraceptive studies), the cumulative incidence is 244 cases per 10,000 women. Although OC use may be a factor in recent breast cancer incidence, there has been little change over the years in reported age-incidence patterns. Therefore, for the present purpose the observed age-incidence data will be assumed to apply in a theoretical population of 10,000 women who are not OC users. The effect of OC use can then be computed for a theoretical population of 10,000 OC users. Thus, among 10,000 non-users, 17 women will have a diagnosis of breast cancer before they reach 35 years of age; among 10,000 oral contraceptive users a total of 26 women will have such a diagnosis, or nine additional women with breast cancer (Table 2). This reflects the baseline rate multiplied by the odds ratio (17 times 1.54 ); the confidence interval indicates that the excess of cases among users is extremely unlikely to be more than 13 women. During the next twenty years, the expected number of breast cancer cases among the 10,000 nonusers will be 244, compared with 232 cases among oral contraceptive users (the expected 244 cases times 0.95 = 232). Among the 10,000 OC users, the computed net reduction would be three breast cancer cases before 55 years of age.
FIGURE3
0.1----~
25
30
35
40
45
50
55
60
Age at Diagnosis (years) Relative risk of breast cancer among DMPA users by age at diagnosis: adjusted relative risks (95% Cl) as reported, 0; weighted linear regression,----
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JANUARY 1995
MEETING THE CHALLENGE OF THE NEWCOMERS
NORGESTREL GROUP ORAL CONTRACEPTIVES THE MARKET LEADER
2
vs
THE NEWCOMERS
MARVELON" ORTHO-CEPP CYCLENl TRI-CYCLENl TRIPHASIL PROVIDES EXCELLENT CYCLE CONTROL WITH LOWER INCIDENCE OF BTB AND SPOTTING 3•4•5 12%
PERCENTAGE OF BREAKTHROUGH BLEEDING EPISODES3•4•5 mMarvelon'/ mOrtho-Cept t wcyclen t
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10
CYCLES
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12%
............................................................................................................ 10
4
3
2
5
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6
2
3
4
Adapted from Kafrissen' Cycles 5 and 6 n/a n = 1,473 women 19,078 cycles
2
3
4
5
6
Adapted from Gauthier et al.' n = 661 women 6,511 cycles
• Marvelon (desogestrellethinyl estradiol) is a registered trademark of Organon Canada Ltd. t Ortho-Cept (desogestrel/ethinyl estradiol), Cyclen and Tri-Cyclen (norgestimate/ethinyl estradiol) are registered trademarks of Ortho-McNeillnc.
TRIPHASIL IS A FORMULATION WITH ANTIANDROGENIC EFFECTS, INCREASING SHBG LEVELS, REDUCING PLASMA ANDROGEN LEVELS AND THUS IMPROVING ACNE 6,7 ".. .this product [Triphasi/] is recommended in women requiring contraception who also have idiopathic acne. "7 PERCENTAGE INCIDENCE OF ACNE'
"The decrease in ovarian/adrenal androgen levels and the increase in SHBG levels, which are distinctly an estrogenic response, indicate that this triphasic formulation has no androgenic properties, but, rather, estrogenic and antiandrogenic effects. "7 n = 491 women
n = 486 women
3,678 cycles
Adapted from Allen et al.
TRIPHASIL HAD A LOWER INCIDENCE OF NUISANCE SIDE EFFECTS 3 TRIPHASIL Amenorrhea Weight gain (more than 2kg) Breast tenderness Discontinuation
0.2% 5.2% 2.2% 6.1%
MARVELON/ ORTHO-CEPT
An unexcelled clinical record
0.9% 16.7% 5.4% 11.9%
"An optimal oestrogen-progestogen ratio... may be more important for the overall effect of the preparation than partial qualities of the hormonal components. "3
' ' ' appear to relate to one of two mechanisms: variability in the number of potential cancer cells seems CASES OF BREAST CANCER THAT MAY BE to explain some risks, such as the international ATTRIBUTABlE TO OC USE differences in incidence; variability in the susceptiBreast cancer Attributable OC Breast cancer bility of those cells may explain hormonally assocases/10,000 cases/1 0,000 RRwith OC cases/10,000 Age at ciated differences, such as the increased risk with users non-users OC users diagnosis use greater age at first birth. 21 There is a short term 1.54 +9 17 <35 years 26 increase in breast cancer risk after a first birth that 244 232 0.95 ·12 35-54yrs be the effect of high hormone levels during may 261 258 All <54yrs ·3 pregnancy. 24 The endogenous hormones appear to induce further growth in breast cells that have already The data on DMPA are based on fewer studies and undergone malignant transformation. Pregnancy also smaller numbers of exposed cases and controls and, confers long-term protection which appears to reflect therefore, the DMPA evidence is less secure than the advanced maturing and terminal differentiation of breast OC effect. The computed attributable risk consists of an tissue with the consequent reduction in malignant excess of 15 cases before age 35 among 10,000 DMPA potential. 24 ' 25 users (1.91 times the expected 17/10,000), and a reduction These endogenous hormonal actions seem to result of 17 cases from age 35 to 54 (0.93 times the expected from both estrogen and progesterone exposure. Studies 244/10,000). Among the 10,000 DMPA users, the comof normal breast tissue have indicated that epithelial proputed net reduction would be two breast cancer cases liferation is maximal in the luteal phase under the influbefore 55 years of age. ence of progesterone. 5•26 Maximal breast tissue growth DISCUSSION also was observed in the last half of hormonal contraception cycles, and these responses to endogenous and In this analysis of the existing literature on the breast exogenous hormones decrease with age, notably during cancer risk attributable to hormonal contraceptives, the the first ten years after thelarche. 5 This change in breast typical risk for OC use was increased for women less than tissue responses is consistent with a shift in the suscep35 years of age, there was a significant downward trend tibility of breast cells to malignant alteration, and given in the OC-associated risk after 35 years of age, and a the long latency period for breast cancer, could underly small net reduction in the computed cumulative breast the cross-over in exogenous hormone risks that was seen cancer risk for OC users compared with non-users. If the after 35 years of age. protection associated with hormone use continues If the influence of endogenous hormones is similar, beyond the age of 54 years, then the overall protective then pregnancy should have an analagous effect. Two effect of hormonal contraception would be much greater. recent large studies 24 ' 25 confirm the indication from earThe oral contraceptives considered in the analysis were lier studies that pregnancy increases the short term risk combinations of estrogenic and progestogenic comof breast cancer in young women, 27 ·'~ Among 91,523 U.S. pounds. Although DMPA has only progestogenic nurses, the increase in breast cancer incidence for parous activity, the observations among DMPA users mirrored women remained elevated for 20 to 30 years after the those among OC users. The analysis confirms the most first birth, compared with nulliparous women, but the likely assumptions about breast cancer risk among oral cumulative incidence to age 70 was lower for the parous contraceptive users, '· 20 ' 22 and it provides precise estiwomen." In a case-control study linking 12,666 breast mates of the downward trend in the OC effect on breast cancer patients and 62,121 age-matched controls from cancer incidence. the Swedish Fertility Registry, pregnancy had a similar The presence of a cross-over from increased risk to dual effect on cancer risk, which was increased trandecreased risk explains in part the conflicting findings of siently after childbirth and decreased in later years. 24 The earlier studiesY This alteration in the effect of exogeSwedish data for uniparous women are shown in Figure nous hormones over time is perplexing, but some recent 4 together with estimates from the present meta-analysis. publications discuss proposed mechanisms that seem bioThus, the existing evidence suggests that endogenous logically and epidemiologically sound. Breast cancer risks
TABLE2
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40
JANUARY 1995
' ' ' FIGURE4 2.0
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+-----+.
and exogenous hormones have comparable effects on breast cancer risk: an increased risk in young women which declines gradually. One explanation for the association between hormonal contraception and breast cancer at a young age is that contraceptive use may delay the first birth. In studies that do not adjust for age at first birth, contraceptive use might express the increased risk that is associated with delayed first birth. This interpretation is unsatisfactory, however, because the association between hormonal contraception and breast cancer was present, although reduced in magnitude, even in studies that adjusted for age at first birth. 11 ·15 ·" A second explanation might be that estrogenic and progestogenic hormones aetas promoters of breast epithelial growth, an action that generally depends on prolonged exposure. A promoter mechanism would be associated with a greater risk after longer duration of exposure, but such an effect was present in only three of the OC studies.w·15 Moreover, in one OC study and one DMPA study, shorter duration of use was associated with increased risk. 7·w A more likely explanation is that pregnancy and hormonal contraception decrease the length of the pre-clinical latent stage in cancers which have already developed, thus causing them to be recognized sooner. Therefore, it seems reasonable to hypothesize that hormonal contraception for the majority of women
JOURNAL SOGC
is harmless or beneficial with respect to breast cancer, although in a small sub-set of women who are as yet unidentifiable, breast cancer is more likely to be diagnosed soon after exposure to these hormones. The existing data do not separate satisfactorily the effect of late first birth from the effect of using oral contraception which is the most common means of delaying conception. Oral contraceptive pills are used by the majority of young women in Western countries. In the UK National Case Control Study, 91 percent of cases and 89 percent of controls had used oral contraceptives for an average total duration of 5.6 years." Because OC use is so prevalent, the attributable risks in Table 2 approximate the population effect, and imply that breast cancer risk should not be a crucial factor in contraceptive decisions for the typical patient. Depo-medroxy progesterone acetate use is much less prevalent ( 12% of the 11,890 controls in the WHO study), and the associated menstrual changes are more problematic, but it provides effective contraception. 1'· 29 On the best available evidence, the DMPA-associated breast cancer risk mirrors that of oral contraception and should not govern clinical or regulatory policy decisions. REFERENCES 1.
Romieu I, Berlin JA. Colditz GA. Oral contraceptives and breast cancer. Review and meta-analysis. Cancer 1990; 66:2253-63.
2.
Rushton L, Jones DR. Oral contraceptive use and breast cancer risk: a meta-analysis of variations with age at diagnosis, parity and total duration of oral contraceptive use.
3. 4.
5.
6.
Br J Obstet Gynaecol 1992;99:239-46. Ewertz M. Oral contraceptives and breast cancer risk in Denmark. EurJ Cancer 1992;28A:1176-81. White E, Malone KE, Weiss NS, Daling JR. Breast cancer among young U.S. women in relation to oral contraceptive use. J Natl Cancer lnst 1994;86:7:505-14. Anderson TJ, Battersby S, King RJB, McPherson K, Going JJ. Oral contraceptive use influences resting breast proliferation. Hum Pathol1989;20:1139-44. Lee NC, Rosero-Bixby L, Oberle MW, Grimaldo C, Whatley AS, Rovira EZ. A case-control study of breast cancer and hormonal contraception in Costa Rica. J Natl Cancer lnst 1987;79:6:1247-54.
41
7.
Miller DR, Rosenberg L, Kaufman OW, Stolley P, Warshauer ME, Shapiro S. Breast cancer before age 45 and oral contraceptive use: new findings. Br J Obstet Gynaecol 1981 ;88:1016-20.
8.
Kleinbaum DG, Kupper LL, Muller KE. Applied regression analysis and other multivariate methods. 2nd ed. Boston: PWS-Kent Publishing Company, 1988:41-79.
JANUARY 1995
' ' ' 9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23. 24.
25. Rosner B, Colditz GA, Willett WC. Reproductive risk factors in a prospective study of breast cancer. Am J Epidemiol 1994; 139:819-35. 26. Meyer JS. Cell proliferation in normal human breast ducts, fibroadenomas, and other ductal hyperplasias measured by nuclear labeling with tritiated thymidine. Hum Pathol1977;8:1:67-81. 27. Bruzzi P, Negri E, LaVecchia C, et al. Short term increase in risk of breast cancer after term pregnancy. Br Med J 1988;297: 1096-8. 28. Williams EM I, Jones L, Vessey MP, McPherson K. Short term increase in risk of breast cancer associated with full term pregnancy. Br Med J 1990;300:578-9. 29. Klitsch M. Injectable hormones and regulatory controversy: an end to the long-running story? Fam Plann Perspect 1993;25:1 :37-40.
Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer lnst 1959;22:719-48. Breslow NE, Day NE. Volume 1: The analysis of casecontrol studies. In Davis W, ed. Statistical Methods in Cancer Research. Lyon: International Agency for Research on Cancer, 1980:136-57. UK National Case-Control Study Group, Chilvers C, McPherson K, Peto J, Pike MC. Oral contraceptive use and breast cancer risk in young women. Lancet 1989;i:973-82. Rosenberg L, Palmer JR, Clarke EA, Shapiro S. A casecontrol study of the risk of breast cancer in relation to oral contraceptive use. Am J Epidemiol 1992; 136:12:1437-44. Stanford JL, Brinton LA, Hoover RN. Oral contraceptives and breast cancer: results from an expanded case-control study. Br J Cancer 1989;60:375-81. Weinstein AL, Mahoney MC, Nasca PC, Leske MC, Varma AO. Breast cancer risk and oral contraceptive use: results from a large case-control study. Epidemiology 1991; 24:353-8. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Breast cancer and combined oral contraceptives: results from a mutinational study. Br J Cancer 1990;61 :110-19. Wingo PA, Lee NC, Ory HW, Beral V, Peterson HB, Rhodes P. Age-specific differences in the relationship between oral contraceptive use and breast cancer. Cancer 1993;71 :1506-17. Paul C, Skegg DCG, Spears GFS. Depot medroxyprogesterone (Depo-Provera) and risk of breast cancer. Br Med J 1989;299:759-62. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Breast cancer and depotmedroxyprogesterone acetate: a multinational study. Lancet 1991 ;338:833-8. Bryant HE, Brasher PMA. Risks and probabilities of breast cancer: short-term versus lifetime probabilities. CMAJ 1994;150:2:211-16. Petitti DB, Porterfield D. Worldwide variations in the lifetime probability of reproductive cancer in women: implications of best-case, worst-case, and likely-case assumptions about the effect of oral contraceptive use. Contraception 1992;45:2:93-1 04. Prentice RL, Thomas DB. On the epidemiology of oral contraceptives and disease. Adv Cancer Res 1987; 49:285-401. Thomas DB. Oral contraceptives and breast cancer: review of the epidemiologic literature. Contraception 1991 ;43:6:597 -642. MacMahon B. Reproduction and cancer of the breast. Cancer 1993;71:3185-8. Lambe M, Hsieh C-C, Trichopoulos D, Ekbom A, Pavia M, Adami H-0. Transient increase in the risk of breast cancer after giving birth. N Engl J Med 1994;331 :5-9.
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